Naltrexone, an opioid receptor antagonist, is an FDA-approved drug used for treating heroin overdose and decreasing alcohol intake in alcoholics. Since the mid-1980's, low dose naltrexone (LDN) has been used off- label for treating HIV infection and preventing AIDS. It has a loyal following of patients and doctors who claim remarkable benefits from LDN, yet there has been little scientific data available to validate or refute LDN efficacy. When administered to untreated HIV-infected individuals, LDN appears to stabilize CD4+ T cell counts, preserve lymphocyte responsiveness to mitogens and delay progression to AIDS. Conceivably, when taken in the early evening LDN may work by causing a normalization of a blunted endogenous circadian opioid surge in HIV-infected individuals, which in turn enhances the function of their immune system. We will take advantage of an availability of SIV-infected macaques that have not received any therapeutic confounding treatments for their SIV infection, having served as control animals for SIV vaccine development research led by various investigators who manage their research through the NEPRC. Rather than euthanize these animals, we will rigorously determine the effect of LDN in attenuating AIDS progression and enhancing immune function. Twenty-four SIV-infected rhesus macaques will be treated with 0, 0.05 or 0.3 mg/kg LDN daily (n = 8/dose). Longitudinal measures of viral RNA loads will be collected, and SIV-specific CD4+ and CD8+ T cell responses to the entire SIV proteome will be quantitated by Elispot and intracellular cytokine staining assays using overlapping SIVmac239 peptides. The profile of memory, activation, and exhaustion markers expressed by circulating memory CD4+ and CD8+ T cells will be determined by a polychromatic flow cytometry panel that includes antibodies to CD3, CD4, CD28, CD95, CCR7, CCR5, CD69, HLA-DR and PD-1, and monitored every 2 weeks. A complete blood count analysis will be performed to determine the total lymphocyte population in whole blood. The total lymphocyte population and the frequency of each subset will be used to calculate cell counts for naive, central memory and effector memory CD4+ T cell populations per l of blood at each time point. Alpha interferon levels will also be measured. The mu-opioid receptor is a major target of naltrexone, and specific nonsynonymous polymorphisms in both the human (N40D) and rhesus monkey (P26R) receptor alter ligand binding and predict naltrexone sensitivity (to curtail alcohol consumption) i both humans and rhesus monkeys in a strikingly parallel manner. Accordingly, we will test the hypothesis that rhesus monkey P26R is a determinant of LDN efficacy in curtailing disease progression in the SIV/macaque model. We will assess genotype/phenotype associations and measure endorphin levels during and following treatment with LDN, revealing circadian patterns in the macaque and effects of LDN and SIV infection on these patterns. If LDN can reduce the progression of AIDS in the highly translational SIV-infected macaque model, the research could validate a low cost and safe intervention to curtail disease progression with little or no side effects.